Oriental Sore

Etude des differents modes de traitement: le traitement traditionnel et les autres, le traitement des recidives, le traitement non medical

When considering the treatment of cutaneous leishmaniasis, one must keep in mind the wide variety of species/subspecies of the parasite involved. These can be expected to have differing pathogenicities and to give rise to different appearances of the skin lesions. To make rinatters even more complex, cutaneous leishmaniasis is recognized to be, like leprosy, a spectrum disease.^ The clinical form taken by the infection depends on the immunologic response of the host. The clinical spectrum of cutaneous leishmaniasis is more complex than that of leprosy not only because of the varying pathogenicities of the parasite involved, but also because there is no clear, universally agreedupon classification ofthe various parts ofthe spectrum.
The host's defense to these intracellular pathogens largely depends on the cell-mediated immune response. On the one hand, the parasite has mechanisms to resist lysosomal cytolysis within the parasitized macrophage. On the other hand, an activated macrophage is able to destroy the parasite. The state of the disease depends on the struggle between these two factors.
The most common form of cutaneous leishmaniasis is acute cutaneous leishmaniasis (ACL), also known as Oriental sore or Baghdad boil. The initial nodular erythematous lesion usually breaks down to form an ulcer. About 90% of such lesions heal spontaneously in weeks or months but usually leave a scar. This primary lesion is at the center of the spectrum. There are many amastigote-filled macrophages earlier in the infection, but as the host becomes sensitized, the cell-mediated response eliminates the parasites. There is a permanent positive reaction to leishmanin (ie, a delayed hypersensitivity response to an intradermal dose of a phenol preparation of promastigotes), and there is said to be a lifelong immunity to reinfection.
At the anergic end of the spectrum is diffuse cutaneous leishmaniasis (DCL). The primary lesion spreads and the parasite is disseminated throughout the whole body surface. The infection is usually very chronic. The result ofthe leishmanin test is negative, and many parasites are found on smear or biopsy specimens. L aethiopica infections are usually associated with DCL.
The hypernergic end ofthe spectrum includes: 1. Chronic cutaneous leishmaniasis (CCL), which follows from ACL that does not heal. There may be erythematous papules at the edge of the lesion. Histology and smears show few or no parasites. There is a tuberculoid type of cellular infiltrate, with macrophages, epithelioid cells, and lymphocytes. These patients have a strong positive reaction to leishmanin. Where ACL "becomes" termed CCL is quite arbitrary. Some authors classify ACL as CCL if the lesions fail to heal in 2 years.^-^ Another author calls CCL the stage when the granulation tissue of the primary lesion has halted its advancement, ie, when the immune response has halted the local spread of the parasite." This author observes that this process takes about 6 months in L tropica major patients in Saudi Arabia. 2. Recurrent cutaneous leishmaniasis (RCL), alsd known as leishmaniasis recidivans, which is different from CCL. RCL occurs at or near the acute lesions that have completely or partly healed.''^ These lesions can appear months or years after the healing of the primary lesion. Histologically, there is also a tuberculoid pattern, with few parasites visible or able to be cultured. Clinically, these lesions have various appearances. Commonly, they spread from the primary lesion. The old scar tissue can have yellow-brown nodules that ulcerate, usually in summer. The edges ofthe lesions may have "applejelly"-like nodules. RCL runs a very chronic course. If the iesions are on the face, as they very often are, the disease Is very disfiguring. The result of the leishmanin test is also strongly positive.
In practice many authors do not make it clear whether they are referring to CCL or RCL. This partly reflects the difficulty in making a clear distinction in many cases between the two forms. RCL is considered when nodules reappear in a partly healed primary lesion, but who is to say what "partly healed" is?

Why Treat Leishmaniasis?
Considering that 90% of primary lesioris of cutaneous leishmaniasis heal spontaneously anyway and that recovery is supposed to confer lifelong immunity, this could be a pertinent question to ask.
In New World cases, there is, of course, the fear of the coiisequerices of L. braziliensis braziliensis infections. L. braziliensis braziliensis infections are always treated. In rural field conditions, the various Leishmania species are difficult to distinguish from each other in smear cultures. There is the hope that genetic recombination techniques can be adapted to field conditions to help in this way in the future. Sohie workers have stressed the importance of distinguishing the different species in order to institute the most appropriate therapy.'' It was by typing that these workers discovered cases of L. braziliensis braziliensis infections in Belize. This feared species previously had not been found in that area.
In the Old World ACL, treatment is desired where there are lesions on exposed parts of the body, especially the face. The healed scars and areas of depigmentation are ugly. Another reason to treat is to prevent secondary bacterial infection of the lesions. Obviously, one also would want to treat in order to prevent the 10% of ACL cases that do not heal from progressing to one of the other chronic forms.
Balanced against the desirability of treatment of Old World ACL are the side effects of treatment. Given the toxic nature of the drugs in current use, most Old World ACL lesions are left untreated.
Infections with L. aethiopica should receive special attention, since they involve large areas of the body surface and tend to have a long course. Healing of these lesions gives rise to severe fibrosis that, for example, may restrict the use of fingers.® Another reason for the need to treat is that treatment is one of the most important methods of controlling the disease in the population.' For controlling anthroponotic cutaneous leishmaniasis in the population, detection and treatment of all human cases are considered very important. For controlling zoonotic cutaneous leishmaniasis, detection of human cases is also important. Control of the vector sandfly and the animal reservoir, the rodent, is also needed; but it is reckoned that when the incidence of zoonotic cutaneous leishmaniasis is less than 1 in 10,000, detection and treatment of human cases alone are sufficient.
For New U/orld cutaneous and mucocutaneous leishmaniasis and L. aethiopica infections, detection and treatment are perhaps the only methods of control. }n the New World, the reservoirs are in the forest and jungles. Many different animals act as reservoirs, and it is impossible to eliminate them all. Wild hyraxes that are reservoirs for L. aethiopica are difficult to contro). Widespread spraying of insecticides would have disastrous effects on ecologic food chains. Movement of human populations away from the jungle fringe is certainly undesirable for cultural, traditional, and socioeconomic reasons.

Traditional Therapies
The current "textbook" method of treating New World cutaneous and mucocutaneous leishmaniasis and Old World cutaneous leishmaniasis (excluding L. aethiopica infections) is with a pentavalent antimonial. The antimonials were first developed for the treatment of schistosomiasis, but they are now used mainly for leishmaniasis. The drugs of choice are sodium stibogluconate and N-methylglucamine antimonate. There are various recommended dosage regimens. Bryceson'° recommends a dose of 0.1 ml of a 34% solution of the drug per kg body weight per day for 14 days. The course can be repeated after a U-day interval. The drug can be given by an intravenous or an intramuscular route. There is reported to be little difference in the efficacy of sodium stibogluconate and N-methylglucamine antimonate in the treatment of mucocutaneous leishmaniasis." A large number of side effects, including nausea, vomiting, diarrhea, skin rashes, headache, and dizziness, are associated with these drugs. More importantly, the drugs are toxic to the liver, kidney, and heart. When these drugs are given intravenously, the patient's electrocardiogram and blood pressure should be monitored, as the drugs can cause cardiac arrhythmias and hypotension. Commonly, the drug is given slowly in an infusion.
The details of the mechanism of action of the antimonials are unclear. Numerous enzymes ofthe parasite are inhibited selectively. Of significance, phosphofructokinase, which catalyzes a rate-limiting step of glycolysis, is inhibited." In this way, production of adenosine triphosphate may be blocked.
For mucocutaneous leishmaniasis, the second line of treatment is with amphotericin B. This is a toxic antibiotic used parenterally for treating systemic fungal infections. The drug should be diluted in 5% dextrose solution and given 1 mg/kg over 6 hours on alternate days. Amphotericin B is very toxic to the kidney. LJrea and urine protein levels should be carefully monitored. Patients often complain of fever, chills, headache, nausea, and nasal swelling. Decreased serum potassium levels are found in 25% of patients receiving the drug. Infusions of amphotericin B are associated with thrombophlebitis. This can be prevented by adding a small amount of heparin to the infusion.
Crofts^^ has recommended amphotericin B as the drug for the first-line treatment of mucocutaneous leishmaniasis. It is claimed that side effects can be reduced by starting treatment with low doses-0.2 mg/ kg. Hydrocortisone and aspirin relieve other side effects. Crofts treated 12 patients for 3-12 weeks until lesions were healed and/or perforations of the nasal septum or palate had fibrosed. In three ofthe patients, treatment with antimonials had failed. Only three patients were followed up (one each for 1, 3, and 4 months) with no recurrence.
Details of the mechanism of action of amphotericin B are not clear. In fungal infections, its action is likely to occur through interaction with ergosterol in fungal membranes. Since Leishmania membranes also have high ergosterol content, it is tempting to think that the drug acts in this way in leishmaniasis also.
Both amphotericin B and pentamidine can be used as second-line drugs to treat cutaneous leishmaniasis, but the severe toxic side effects should be seriously considered. Pentamidine, an aromatic diamidine, is given intramuscularly at about 4 mg/kg/day for 14 days. Besides causing vomiting, hypotension, and tachycardia, it is also toxic to the liver, kidney, and pancreas. Pentamidine mesylate, compared with pentamidine isethionate, is especially pancreatotoxic, causing transient diabetes meilitus.'" The mechanism of action of pentamidine is not clear. In the treatment of early African trypanosomiasis, the selective action of pentamidine is believed to be to block parasite nucleic acid synthesis in a non-intercalative way.
Infections with L. aethiopica pose a special problem because they are refractory to the normal regimens of antimonials. Bryceson,^^ treating 33 cases of DCL caused by L. aethiopica, found N-methylglucamine antimonate to have some effect only at high doses. Instead, he recommends pentamidine or amphotericin B, both of which are consistently effective in such infections. Treatment must be prolonged even after apparent elimination of parasites, as relapses have been observed up to 15 months later. Bryceson also made the interesting observation that before the patients are finally cured, they relapse in a form that has a tuberculoid histology and convert to leishmanin-positive from a previously negative state. Chemotherapy is usually unsuccessful until this conversion.
Chulay,^* however, recommends using high doses of sodium stibogluconate to treat L. aethiopica infections. He claims that this is effective, with side effects kept at a reasonable level. He used up to 40 mg/kg/ day of antimony to treat three Kenyan patients with lesions of 5-9 months' duration. In normal regimens, a maximum of 10 mg/kg antimony is given daily. No parasites were detectable at 11-15 months, and no lesions had recurred by 18 months. However, this report lacks a longer follow-up and a larger number of cases. There is also the possibility that the lesions had healed spontaneously.
The aforementioned drugs are unsatisfactory not only because of their side effects but also because their administration is cumbersome and expensive. Patients from distant areas have to travel to an inpatient center to be monitored. Obviously, there is a great need for a safe, effective, and quick method of treatment. Many other methods have been suggested, but they have not stood or have yet to stand the test of time. Treatment trials of leishmaniasis are difficult to assess. Spontaneous healing has to be taken into account. Different workers have different criteria for cure or "improvement"; it may be based on clinical findings or smearor biopsy cultures. Many of the reports are based on small groups of patients or on anecdotal reports. No double-blind trials have been reported. These factors make the results extremely difficult to interpret. Because of the threat to life of mucocutaneous leishmaniasis, most workers have felt it unethical to treat with methods other than the established drugs. Bearing this in mind, we will discuss other methods that have been tried.

Other Therapies
An obvious approach in the search for new drugs is to try drugs already in the market that are used for other conditions. 1. Metronidazole. Metronidazole is used in the protozoal infections amebiasis and trichomoniasis. Its selective toxicity depends on the nitro-group of the drug being reduced only by enzymes in the anaerobic/microaerophilic environment of the interior of the parasite: the protozoal cell is deprived of reducing equivalents, and the reduced form of the drug degrades DNA and prevents nucleic acid synthesis. Beltran'^ reported clinical cure in 21 of 30 patients with cutaneous leishmar\iasis in Mexico. Pederson'* and Long" both report anecdotal cases of apparent cure by metronidazole. Griffiths^" had a trial of 24 cases of cutaneous leishmaniasis in Iran. However, there were only two cases of complete cure (at 12 and 21 months after the start of treatment), six incomplete cures, ten with no change, and six "lost patients." Wahba^' found the drug ineffective in six cases in the Middle East.
The earlier reported successes could be accounted for by spontaneous cure. Although there was much interest in the drug in the 1970s, it now appears that metronidazole is unlikely to play a primary role in the therapy for leishmaniasis.

2.
Nifurtimox. This is the drug of choice in American trypanosomiasis (Chagas' disease), where it is active against the amastigote phases of the parasite. Like metronidazole, its selective toxicity is probably due to the reduction of a nitro-group on the drug inside the parasite. With a dosage of 10 mg/kg/day for 30 days, Marsden^f ound clinical cures in 6 oi^ 13 New World cutaneous leishmaniasis cases but only in 2 of 13 mucocutaneous leishmaniasis cases. The same group had another opportunity to try nifurtimox in an area where mucocutaneous leishmaniasis was common. This was ethically possible because N-methylglucamine antimonate was temporarily unavailable. Eighteen patients entered into the trial had only skin lesions. The Leishmania species was not identified by culture, and it was only assumed that, because of being in an endemic area, L. braziliensis braziliensis was involved. Clinical cures were achieved in five of eight patients on 8-10 mg/kg/day nifurtimox for 120 days and in 6 of 10 patients on 20 mg/kg/day nifurtimox for 10 days.^^ By comparison, the rate of spontaneous cure of such lesions in this area is only 50% in 6 months. On four patients with mucosai lesions, nifurtimox had no effect.^' Side effects were more common and more severe when the higher dose was used. These included anorexia, weight loss, insomnia, and personality changes. However, the low-dose regimen takes too long to administer.

3.
Rifampicin. Rifampicin is a commonly used drug in tuberculosis and leprosy. Rifampicin at 100-200/ig/ml is found to inhibit the transcription of L. tarentolae kinetoplast maxicircle DNA." At this concentration the drug also alters the morphology of L. tropica promastigotes^â nd, in vitro in 4 days, reduces the parasite survival index (PSI) of L tropica amastigotes to 10% compared with controls.^Î n one of the earlier trials with rifampicin using 1200 mg/day, clinical cure occurred in 3-8 weeks in 41 of 46 cases of cutaneous leishmaniasis.^^ The other five cases were treatment failures or patients "lost" to follow-up. Another Middle East group, using 600 mg/day rifampicin, reported cjinical cure in 4-16 weeks in 9 of 13 patients with cutaneous leishmaniasis.^" The other four patients were lost, as they had to leave the country.
Rifampicin (600-1200 mg/day) produced protozoologic cure in six of eight cases of cutaneous leishmaniasis in Jsrae). The criteria for cure in these six patients are 10 consecutive days of smear and culture negativity." However, this group later reported less satisfactory results with rifampicin on seven further patients.^" White'' reported on an anecdotal case of treatment failure with rifampicin.
Rifampicin has been tried in combination with other drugs. The Israeli group report that rifampicin is more effective when combined with isoniazid.^" In a trial of six cases of L tropica major cutaneous leishmaniasis, three cases became protozoologically negative in 28 days and another two cases at 48 days. Peters^^ reports an anecdotal case of successful treatment of L major amazonensis diffuse cutaneous leishmaniasis with rifampicm and isonrazi'd.
Van der Meulen" reports that, compared with pentamidine, a combination of isoniazid (300 mg/day), rifampicin (600 mg/day), and amithiozone (150 mg/day) for 8 weeks is not effective in the treatment of L. aethiopica infections. In his small trial, pentamidine gave clinical and protozoologic improvement in all six patients, whife the test regimen gave only one improvement in six patients.
Rifampicin has also been combined with sodium stJbogJuconate and bas been reported to potentiate the effect of sodium stibogluconate when used to treat cutaneous leishmaniasis." Of 16 cases on 600 mg/day sodium stibogluconate for 12 days, there were 7 clinical improvements; and of 16 cases on 600 mg/day rifampicin for 21 days, there were 8 improvements. When the 17 "treatment failures" from the two above groups were put on a combination of the two drugs, 13 of them got better. The result of this trial is questionable because one can argue that the "treatment failures" were merely slow to respond to the first treatments.
Experimentally, rifampicin has been combined with amphotericin B in treating L major and L amazonensis infections in mice. This combination had no effect," but of course this could merely reflect the inappropriateness of the mouse infection model.
The above results suggest that rifampicin can play only a limited role in the therapy for leishmaniasis. However, further trials are warranted to try to define what this limited role can be.
Metronidazole, nifurtimox, and rifampicin are common(y quoted in current textbooks as probable alternative drugs to the established toxic ones. At present, none of the three can be said to be effective when used as a sole agent. There is scope, however, for combination with sodium stibogluconate or pentamidine, thus lowering the doses required of these toxic drugs. Rifampicin and nifurtimox could have important roles for use in maintenance therapy in L. aethiopica and L. braziliensis braziliensis infections, respectively. These infections demand prolonged treatment to prevent re-Japse. It is useful to use oral agents like rifampicin or nifurtimox that can be administered at home away from an inpatient center.

B-Aminoquinojines.
This class of drugs is used in the treatment of malaria. Interest has been directed at this group because a derivative, WR 6026, is found to have exceptional efficacy, compared with N-methylglucamine antimonate, in the L donovanz-hamster model of visceral leishmaniasis.^^ In vitro, the 8-aminoquinolines have been found to be active against L. tropica within human macrophages." Although WR 6026 is active in vivo in the experimental L. donovani infection, however, it has been found to be inactive in L majormouse model.'* No convincing clinical trials have been reported.

5.
Levamisole. Levamisole is used in nematode infections because of its effects on the energy metabolism of the metazoan parasites. Its use in leishmaniasis is dependent on a separate property of the drug: its immunopotentiating effect on T cells." Butler observes that even in an endemic area, the prevalence of cutaneous leishmaniasis is low. He believes that most local inhabitants are inoculated in early life with the parasite by sandflies and have subclinical infections. This gives long-term immunity. Butler proposes that clinical cutaneous leishmaniasis infections in later life are due to a declining cell-mediated immune response, which can be potentiated by levamisole. In his trial, 28 patients were cured with levamisole without other medication. This interesting proposal requires further investigation.
6. Phenothiazines. The phenothiazines, which include chlorpromazine, are psychoactive drugs established in the treatment of psychiatric disorders. It was a surprise to find that they have antileishmanial (and antitrypanosomal) effects. Pearson" found chlorpromazine effective both in vitro and in vivo using a L donovanZ-hamster infection model of visceral leishmaniasis. The parasiticidal concentrations are about 10 times higher than the drug plasma concentrations used in psychiatric cases." However, the author pointed out that since the drug is lipophilic, achievable tissue concentrations are higher than plasma concentrations. Berman"" found that at achievable tissue levels of chlorpromazine, all L tropica in human macrophages in vitro were eliminated, Seebeck"' proposed that the selective activity of the phenothiazines or trypanosomes is on their unique tubulin of their microtubules. Details of selective activity on Leishmania are unclear.
Henriksen"^ treated three patients with L aethiopica diffuse cutaneous leishmaniasis with topical chlorpromazine. Inflammation improved, and parasite smears were negative after 1 month of treatment."^ Although this method of treatment is attractive, its efficacy has yet to be investigated further. There was no indication in the report of the length of follow-up. Also, it is considered dubious to base cure on non-isolation of the parasite. Undetected parasites can persist."' 7. Allopurinol. Allopurinol is used in gout prophylaxis and hyperuricemia. It is observed to prevent growth of Leishmania species and Trypanosoma cruzi in vitro.** It also augments the antileishmanial effect of sodium stibogluconate in vitro.*" A metabolite of allopurinol, which degrades RNA, is produced in these protozoan cells that is not produced in mammalian cells.
The drug (50 mg/kg/day) was effective in curing four of five monkeys infected with L. braziliensis panamanensis.*^ However, in another report using experimental animals, allopurinol ribonucleoside (a related compound of allopurinol) was found to have low in vivo activity against L major and other Leishmania species causing cutaneous leishmaniasis.'" Allopurinol was successful in curing 6 of 10 patients with visceral leishmaniasis who had previously failed with sodium stibogluconate."' Oral allopurinol (15 mg/ kg/day for 14 days) produced questionable cure in two of five patients with mucocutaneous leishmaniasis. There was clinical cure in the two patients after 2 months from start of treatment, but there was still a significant fluorescent antibody titer at 1 year."T here have also been more "rational" approaches to the search for better antileishmanial agents.
The established antileishmanial drug, amphotericin B, probably acts by interacting with ergosterol in the Leishmania membrane. Four relatively nontoxic imidazoles, which also interact with ergosterol, were tried for their activity against L. tropica in human macrophages in vitro.^^ Ketoconazole, an antifungal drug, and hydrolyzed ketoconazole were observed to be effective.
Urcayo"' reports on oral ketoconazole (400 mg/day for 3 months) being effective on six Nicaraguan patients with early skin lesions. The drug was well tolerated, and there was no overt disease at 3 months after cure. In another report, five of eight L. ma/or-infected patients were cured clinically and protozoologically after 6 weeks of ketoconazole treatment.^" Follow-up 1 month later showed no disease. In an anecdotal case report, one of two lesions on a patient on which miconazole (an imidazole) was applied topically healed in 1 week.^' Prednisolone and chloramphenicol were applied to the other lesion, and this took 6 weeks to heal.
Polyamines are multiply amine-substituted straightchain aliphatics that have important functions in the growth of trypanosomes and Leishmania. The polyamines include putrescine, spermidine, and spermine. Inside the protozoan cell, the polyamines are likely to be involved in stabilizing nucleic acids, transfer RNA, or the ribosomes. The levels of polyamines rise in the skin and spleen of mice infected with L tropica major, and the levels fall when the mice are treated with pentamidine." In the parasite, polyamines are synthesized from arginine and ornithine, and the rate-limiting step in the synthesis is catalyzed by ornithine decarboxylase (ODC). Blocking polyamine synthesis by use of inhibitors of ODC, eg, difiuoromethylornithine (DFMO), should be attempted in experimental Leishmania infections. DFMO is found to reduce parasitemia in T. 6ruce/ brucei infections in mice."-^" This effect is found to be negated by the administration of exogenous polyamines." One of the pathogenic factors of the Leishmania is that they are able to survive inside the host macrophages. In vitro, when L tropica promastigotes are taken into mouse macrophages, superoxide radicals and hydrogen peroxide are produced.^^ The parasite is able to survive these activated oxygen radicals. L tropica has no catalase, but the parasite is probably protected because it is found to have a high level of superoxide dismutase (SOD). It is found that the L tropica SOD is insensitive to diethyldithiocarban, which inhibits mammalian cell SOD. Differences in properties of SOD of the parasite and the mammalian host may be exploited to find a selective target for chemotherapy.
It is found that L. major mexicana amastigotes have a high proteinase activity compared with L major mexicana promastigotes and other protozoan or mammalian cells. These are mostly cysteine proteinases and are found in organelles named megasomes in the L. major mexicana amastigotes.^^ The effect of the inhibition of the cysteine proteinases by the peptide analogues antipain and leupeptin have been investigated in vitro. In 7 days at 100 mg/L, antipain is seen to reduce by eightfold the percentage of infected mouse macrophages, and to 5% the number of amastigotes, as compared with a control. At 1 mg/L, antipain and leupeptin, like pentamidine, stop the in vitro multiplication of the parasite. No observable effects on the host cells were noticed. In vivo studies should be done to see the efficacy of these antileishmanial agents, L. donovan/accumulates L-proline and D-glucose into its interior by a proton electrochemical gradient across its surface membrane. This is partly driven by an H"Â TPase in the membrane. Mammalian cell membrane is not organized in this way. Zilberstein^' found that the antidepressant clomipramine killed promastigotes and amastigotes of both L major and L donovani in mouse macrophages in vitro. There were no apparent effects on the host cell. Clomipramine is believed to inhibit the H+ ATPase in the membrane ofthe parasite. This effect of disrupting the parasite surface membrane proton electrochemical gradient may be exploited for chemotherapy.
There is a preliminary report on the use of an immunologic approach in treating three Iranian patients with cutaneous leishmaniasis.^" "Transfer factor" is a dialyzable extract of leukocytes obtained from healthy donors who have recovered from cutaneous leishmaniasis. This factor is injected subcutaneously near the skin lesions on the patient. All three patients had longstanding chronic cases. The lesions reappeared but again improved when therapy was recommenced. Follow-up at 8 months after cure was good in all three cases. The transfer factor is likely to have an effect on the cell-mediated immune response. Further trials of this method are needed before its efficacy can be judged.

Treatment of Leishmaniasis Recidivans
Many of the drug therapies that are effective for ACL are less effective for leishmaniasis recidivans (RCL). It is believed that this is due in part to the structure of the tuberculoid lesions. These have a dense cellular infiltrate and, later, dense scar tissue, surrounding small islands ofthe parasite. These pockets are not penetrable by the drugs.
Steroids have been injected near or at the lesion to shift the hypernergic activity toward a normogenic response.^'-" This treatment is, however, very painful. Cohen reports adding emetine to steroids to successfully treat an anecdotal case that had failed with amphotericin B." Emetine is usually used in the treatment of severe, life-thi-eatening cases of amebiasis. lysosomotropism There has been some interest in increasing the efficiency of delivery of the drug to the intracellular parasite. Liposomes are small vescicles (of diameter greater than 25 nm) that form spontaneously when phospholipids are dispersed in an aqueous media. Antileishmanial agents entrapped in liposomes, used experimentally in visceral leishmaniasis, have been shown to have greater efficacy than the free drug.*""" It was thought that the liposomes were phagocytosed by the infected macrophages in the spleen and liver and were then fused with the vacuoJe containing the parasite, thus delivering the drug directly to the parasite.
Later, it was found that Iiposome-entrapped sodium stibog/uconate was more effective than free sodium stibogluconate in experimental cutaneous leishmaniasis also.^* It is shown that the drug is taken up by circufating mononuc(ear phagocytes. These drug-/aden macrophages then enter the skin lesion and have increased ability to eliminate the parasites.*^ This is shown by experiments where (iposome-entrapped sodium stibogluconate is injected into a donor mouse. After 24 hours, whole blood from this uninfected donor is transfused into an infected mouse. This procedure had the same effect as Iiposome-entrapped sodium stibogluconate injected directly into the infected mouse and was more effective than blood from donors that had been injected with free or no drug.
if such Iiposome-entrapped drugs are designed for humans, then lower and less toxic doses could be used.

Nonmedica] Treatment of Leishmaniasis
Plastic surgery has for a long while had an important role to play in treating disfiguring scars, especially scars of leishmaniasis recidivans.*®'*' In these cases, the patients already would have been on chemotherapy for some time. If any amastigotes are left at the edge of the original lesion during surgical removal, then there is the chance of a relapse.
Surgery as a primary measure for treating ACL is unorthodox, but two series have been reported re-y Currie treated 78 lesions (in 30 patients) in Afghanistan/Pakistan by surgical curettage under local anaesthetic. There were 73 successes, with wound healing within 4 weeks. Azab treated 35 lesions (in 20 patients) in Saudi Arabia. In some cases, skin flaps or free grafting was used. At 8 to 12 months follow-up, there were no lesions on any of the patients. The author claims good cosmetic results, with no hypopigmentation or hyperpigmentation, keloids, or hypertrophic scars. Surgical treatment is quick, cheap, and simple with few side effects and, in simple cases, requires only one or two visits to the clinic by the patient. In early cases, surgery removes the lesion before it enlarges to a size that will produce undesirable scarring. It is recommended that patients be treated about 4 months after the lesions appear in order to enable time for immunity to develop.
Leishmania organisms are very thermosensitive. Both heat and cold treatment have been tried. Heat treatment has been used quite often in the past,^^ although it has not achieved widespread popularity. Mutiga describes clinically successful treatment of two ACL cases by wrapping hot water-soaked fabric around the lesions and successful treatment of three ACL cases by combined ultraviolet light and infrared therapy.^Ŝ pontaneous healing cannot be excluded in these cases.
In a recent publication, Neva'''* describes ieffective heat treatment of three patients in the Dominican Republic who had L. mexicana diffuse cutaneous leishmaniasis of 6-13 years' standing. Over a few days, the patient spends a total of 20 hours in a bath of 39-41 C. There are clinical improvement and negative biopsy specimen cultures and histology. This method is still at an early experimental stage but, if proved effective, will be very useful since the diffuse disease is usually refractory to chemotherapy. However, the technique seems very cumbersome to administer. The same author reports that heat treatment is not effective in treating acute primary lesions caused by /.. tropica and L. braziliensis species.
In recent years, there have been numerous reports on the use of cryosurgery in leishmaniasis. Cold treatment has an advantage over heat treatment in that it tends to cause less inflammation to the surrounding tissues.
Bassiouny^^ reports the successful treatment of 30 South American patients using cryotherapy with a carbon dioxide cryomachine. Follow-ups of 27 patients at 1 year and 3 patients at 6 months show no recurrence. In the treatment, the probe-tip is applied for less than 60 seconds. In this report, at 5 weeks after treatment, the cosmetic result is good. There is little scarring because cryotherapy leaves an intact collagenous framework. However, cryotherapy can result in permanent pigment changes in dark-skinned people. Faber^^ has also reported success and good cosmetic results in treating four cases of cutaneous leishmaniasis. Cryotherapy is short and quick and gives relatively little discomfort. Since there is no necrotic effect on cartilage, cryotherapy is suitable for use in lesions of the nose.
Surgei-y and cryosurgery are useful for rijral populations who need to travel long distances foi' treatment and for migrating populations. They may also spare preghant and weak patients from toxic di^ug effects. However, these treatments can play only an adjunctive or palliative role in L. braziliensis braziliensis infections. This is because there is usually early systemic spread of the parasite to the mucosa, although the mucosai lesions may not appear until much later.Ĉ onclusion The mainstay of treathient for cutaneous leishmaniasis and mucocutaneous leishmaniasis is with peritavalent antimohials, pentamidine and arpphotericiri B. Other less toxic drugs cannot at present replace the use of the established drugs, but can have a role in supplementary or maintenance therapy. Surgery and cryosurgery for ACL is quick, simple, appears effective and offers an attractive alternative to chemotherapy. Treatment of human cases is a most important method of controlling mucocutaneous and cutaneous leishmaniasis in the population: